Warfarin and Superwarfarin Toxicity Medication

Packed red cells and FFP may be required for immediate management of life-threatening hemorrhagic complications. An FFP volume of 15 mL/kg is typically sufficient to completely reverse coagulopathy. Alternatives to FFP treatment include administration of rFVIIa or PCC. Readers should be aware of the large heterogeneity in the literature for PCC as there are at least 10 different PCC formulations.

Early PCC products, including those currently available in the United States, contain factors II, IX, and X. Newer products include factor VII. Some contain protein C and S, protein Z, antithrombin II, and/or heparin. Across 4-factor products, however, there appears to be rapid reversal of coagulopathy within 10-30 minutes.^[17]

Recombinant factor VIIa has been shown to correct INR within hours.^{[18, 19, 20]} The potential benefits of rFVIIa or PCC over FFP include rapid administration (because rFVIIa and PCC do not have to be thawed), smaller infusion volumes, and decreased risk of transfusion-associated adverse reactions. Studies have shown improvement only of secondary endpoints, such as intracranial hematoma size, total volume of blood products, and time to operative intervention.^{[19, 20, 21, 22]}

However, no mortality benefit has yet been demonstrated for rFVIIa or PCC over FFP. Additionally, there is a poorly described risk of thromboembolic events from these products. On the basis of the current literature, the precise role of rFVIIa or PCC in the treatment of warfarin and superwarfarin is unclear.

Use rFVIIa or PCC only after consultation with the local poison control center or medical toxicologist, since dosing is still not firm and it has significant variability from one institution to another. Intravenous bolus doses in clinical trials for rFVIIa (NovoSeven) anticoagulation reversal have widely varied from 5-320 mcg/kg. Mean doses ranged from 16.3-87.35 mcg/kg. PCC (Feiba VH) dosage for hemorrhage caused by blood coagulation disorders associated with inhibitors of factor VIII, XI, or XII vary widely and may differ from patient to patient, with no correlation to the patient's inhibitor titer. Response may also vary between different types of hemorrhage (eg, joint hemorrhage vs CNS hemorrhage).

For PCC, as a general guideline, a dosage of 50-100 units/kg IV at 12-hour intervals is recommended. The lower range is recommended for joint or mucous membrane bleeding. For soft tissue bleeding, 100 units/kg every 12 hours is recommended. For severe hemorrhage (eg, CNS bleeding), 100 units/kg every 12 hours is recommended, although a more frequent dosing interval (ie, 6 h) may be indicated until clear clinical improvement is achieved.

Vitamin K ₁ is the only effective antidote for long-term management, but reversal of anticoagulation takes several hours. Excellent oral bioavailability and rapid absorption substantially negate any potential advantage of other routes of administration.^[23] Vitamin K ₁ IV has been reported to cause acute cardiovascular collapse, presumably caused by an anaphylactoid reaction. Intramuscular or subcutaneous administration may cause hematoma in anticoagulated patients. In the authors' opinion, oral administration, when possible, is preferred.

Class Summary

Activated charcoal is empirically used to minimize systemic absorption of the toxin.

Vitamin K₁ is used in the management of poisoning and overdose, in the prevention of toxic effects, and in metabolic disorders in which toxic substances accrue.

Activated charcoal (Actidose-Aqua, Char-Caps, Kerr Insta-Char)

Activated charcoal is the emergency treatment used for poisoning caused by drugs and chemicals. A network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Activated charcoal does not dissolve in water.

Administer activated charcoal to patients who present 1-2 hours postingestion or to patients in whom co-ingestants may delay gastric emptying or gut motility; minimal benefit is expected if more than 4 hours have passed since the ingestion.

Phytonadione (MEPHYTON)

Phytonadione (Vitamin K1) can overcome competitive block produced by warfarin and other, related anticoagulants. (Note that vitamin K3 [menadione] is not effective for this purpose.) The clinical effect is delayed for several hours while liver synthesis of clotting factors is initiated and plasma levels of clotting factors II, VII, IX, and X are gradually restored.

Vitamin K1 is not to be administered prophylactically; use only if evidence of anticoagulation exists. The required dose varies with the clinical situation, including the amount of anticoagulant ingested and whether it is a short-acting or long-acting anticoagulant.